NM_003839.4:c.-39G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003839.4(TNFRSF11A):c.-39G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.262 in 964,284 control chromosomes in the GnomAD database, including 34,255 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.28 ( 5996 hom., cov: 31)

Exomes 𝑓: 0.26 ( 28259 hom. )

Consequence

TNFRSF11A
NM_003839.4 5_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.25

Publications

6 publications found

Variant links:

Genes affected

TNFRSF11A (HGNC:11908): (TNF receptor superfamily member 11a) The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptors can interact with various TRAF family proteins, through which this receptor induces the activation of NF-kappa B and MAPK8/JNK. This receptor and its ligand are important regulators of the interaction between T cells and dendritic cells. This receptor is also an essential mediator for osteoclast and lymph node development. Mutations at this locus have been associated with familial expansile osteolysis, autosomal recessive osteopetrosis, and Paget disease of bone. Alternatively spliced transcript variants have been described for this locus. [provided by RefSeq, Aug 2012]

TNFRSF11A Gene-Disease associations (from GenCC):

Paget disease of bone 2, early-onset
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
autosomal recessive osteopetrosis 7
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, Orphanet
familial expansile osteolysis
Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
dysosteosclerosis
Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet
osteosarcoma
Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp

TNFRSF11A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.012).

BP6

Variant 18-62325314-G-A is Benign according to our data. Variant chr18-62325314-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 259177.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.338 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF11A	NM_003839.4 link	c.-39G>A		5_prime_UTR_variant	Exon 1 of 10	ENST00000586569.3	NP_003830.1	Q9Y6Q6-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
TNFRSF11A	ENST00000586569.3 link	c.-39G>A	5_prime_UTR_variant	Exon 1 of 10	1	NM_003839.4	ENSP00000465500.1	Q9Y6Q6-1
TNFRSF11A	ENST00000269485.11 link	c.-39G>A	5_prime_UTR_variant	Exon 1 of 7	1		ENSP00000269485.7	Q9Y6Q6-2
TNFRSF11A	ENST00000592013.1 link	n.-12G>A	upstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.278

AC:

40719

AN:

146588

Hom.:

5994

Cov.:

show subpopulations

Gnomad AFR

AF:

0.343

Gnomad AMI

AF:

0.301

Gnomad AMR

AF:

0.228

Gnomad ASJ

AF:

0.223

Gnomad EAS

AF:

0.104

Gnomad SAS

AF:

0.166

Gnomad FIN

AF:

0.262

Gnomad MID

AF:

0.239

Gnomad NFE

AF:

0.275

Gnomad OTH

AF:

0.275

GnomAD2 exomes

AF:

0.0645

AC:

371

AN:

5752

AF XY:

0.0636

show subpopulations

Gnomad AFR exome

AF:

0.153

Gnomad AMR exome

AF:

0.0435

Gnomad ASJ exome

AF:

0.0594

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0679

Gnomad NFE exome

AF:

0.100

Gnomad OTH exome

AF:

0.0479

GnomAD4 exome

AF:

0.259

AC:

211770

AN:

817590

Hom.:

28259

Cov.:

AF XY:

0.258

AC XY:

98727

AN XY:

382418

show subpopulations

African (AFR)

AF:

0.334

AC:

5095

AN:

15242

American (AMR)

AF:

0.108

AC:

319

AN:

2944

Ashkenazi Jewish (ASJ)

AF:

0.200

AC:

1116

AN:

5590

East Asian (EAS)

AF:

0.0824

AC:

331

AN:

4018

South Asian (SAS)

AF:

0.150

AC:

2852

AN:

18966

European-Finnish (FIN)

AF:

0.178

AC:

173

AN:

972

Middle Eastern (MID)

AF:

0.233

AC:

390

AN:

1674

European-Non Finnish (NFE)

AF:

0.263

AC:

195073

AN:

741228

Other (OTH)

AF:

0.238

AC:

6421

AN:

26956

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.428

Heterozygous variant carriers

6300

12601

18901

25202

31502

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.278

AC:

40733

AN:

146694

Hom.:

5996

Cov.:

AF XY:

0.273

AC XY:

19490

AN XY:

71404

show subpopulations

African (AFR)

AF:

0.343

AC:

14027

AN:

40906

American (AMR)

AF:

0.228

AC:

3373

AN:

14790

Ashkenazi Jewish (ASJ)

AF:

0.223

AC:

757

AN:

3388

East Asian (EAS)

AF:

0.104

AC:

532

AN:

5112

South Asian (SAS)

AF:

0.165

AC:

796

AN:

4820

European-Finnish (FIN)

AF:

0.262

AC:

2245

AN:

8560

Middle Eastern (MID)

AF:

0.250

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.275

AC:

18098

AN:

65880

Other (OTH)

AF:

0.274

AC:

560

AN:

2042

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

1437

2874

4311

5748

7185

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.285

Hom.:

773

Bravo

AF:

0.274

Asia WGS

AF:

0.171

AC:

485

AN:

2834

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 19, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Bone Paget disease

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Osteopetrosis

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.97

PhyloP100

2.2

PromoterAI

-0.19

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Mutation Taster

=299/1

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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NM_003839.4:c.-39G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over